Intervention

151 patients were allocated to oral cyclosporine at an initial daily dose of 2.5 mg/kg
body weight with a dose increase to 5 mg after 1 week. Thereafter, the dose was increased
to a maximal daily dose of 15 mg/kg in order to attain a whole-blood trough concentration
of 200 ng/mL. 154 patients were allocated to placebo capsules. All patients continued
to receive their usual therapy for Crohn disease.

Main outcome measures

Clinically important worsening of Crohn disease, defined as a 100-point increase in
the Crohn's Disease Activity Index; use of prednisone and 5-aminosalicylates mean
quality-of-life score; and the need for surgery.

Main results

91 patients (60%) receiving cyclosporine had worsening of disease compared with 80
patients (52%) receiving placebo (P = 0.10) (Table). The mean time to the worsening of the disease was 338 days in the
cyclosporine group and 492 days in the placebo group. No differences were shown for
overall mean scores on the Crohn's Disease Activity Index (P = 0.31), mean quality-of-life scores (P = 0.49), and the use of prednisone and 5-aminosalicylates. Similar numbers of patients
in the cyclosporine and placebo groups had surgery (25 vs 24). The most common adverse
effects in the cyclosporine group were paresthesias, headaches, and hypertrichosis.

Conclusion

The addition of low-dose cyclosporine to usual treatment for Crohn disease did not
improve symptoms or reduce the need for other forms of therapy.

Sources of funding: Sandoz Pharma, Quebec, Canada, and Medical Research Council of
Canada.

Commentary

Cyclosporine, which selectively blocks the activation of T-helper and cytotoxic lymphocytes,
has revolutionized organ transplantation and is used to treat several autoimmune disorders.
This drug is now being explored as therapy for inflammatory bowel disease. Two well-designed
and well-executed double-blind, controlled trials are reported here. An editorial
in the same journal is recommended to readers (1).

The study by Lichtiger and colleagues is a continuation of their previously published
work suggesting an important role for cyclosporine in the treatment of severe ulcerative
colitis refractory to steroid therapy. In this study, the response to intravenous
infusion of cyclosporine, 4 mg/kg per day, was rapid and impressive. The response
was assessed using a clinical activity score. Patients in the placebo group who were
switched to cyclosporine also had important improvement in symptoms. Although not
documented in this study, endoscopic and histologic improvement in these patients
has been reported by these authors.

On the other hand, Feagan and colleagues, in a well-designed study, have shown the
lack of effectiveness of cyclosporine at a low oral dose in patients with Crohn disease.
The size of the population enrolled in the study was adequate for statistical analysis
and the outcome measures were based on well-accepted parameters used in similar studies.
Patients were followed for a period of 18 months, which seems to be adequate to evaluate
effectiveness of therapy in a chronic disorder such as Crohn disease. Cyclosporine
did not improve symptoms or reduce the requirement for other medications. Interestingly,
no relation existed among cyclosporine dose, blood levels, or clinical outcome.

What can clinicians conclude from these studies and what will be the role of cyclosporine
in inflammatory bowel disease? Intravenous cyclosporine appears to be effective in
the treatment of acute ulcerative colitis. Further studies are needed to establish
the value of cyclosporine at a lower dose (2 mg/kg), to assess use of this drug as
the initial treatment (rather than use in patients who are unresponsive to corticosteroids),
and to provide endoscopic and histologic follow-up for a larger number of patients.
If these studies show efficacy, cyclosporine will be the first drug since steroids
to be introduced in the last 4 decades for treatment of acute ulcerative colitis.

As for the role of cyclosporine in Crohn disease, the jury is still out. Cyclosporine
most likely will not be of wide use in this disease. 1 controlled trial (2) using higher doses of cyclosporine showed a beneficial effect; however, the toxicity
associated with higher doses cannot be ignored. The reason for the lack of responsiveness
in Crohn disease and especially the worsening of symptoms in most patients treated
with cyclosporine, as documented in this study, deserve further investigation, possibly
in the laboratory rather than in the clinic. The good news in Crohn disease treatment
is, however, the documented effectiveness of other immunosuppressive medications,
such as azathioprine and mercaptopurine. Newer delivery systems and a whole new generation
of 5-aminosalicylate derivatives could offer new horizons for the treatment of Crohn
disease.

As with all other immunosuppressive drugs, the adverse effects of cyclosporine need
to be considered. Short-term side effects are well known. More worrisome, though,
are the long-term effects of cyclosporine in patients with inflammatory bowel disease.
Unfortunately, both ulcerative colitis and Crohn disease may predispose the colon
to develop malignancy. What will be the effect of short-term and long-term use of
cyclosporine on organs that are already predisposed to develop malignancy? Although
cyclosporine has been used in other autoimmune disorders and in transplantation, none
of these disorders has the inherent tendency to predispose patients to develop malignancies
as does ulcerative colitis. Cyclosporine (or other immunosuppressive drugs) in association
with allograft transplantation is thought to be an independent risk factor for some
malignancies, but increased cancer of the colon has not been shown. The question of
when to use cyclosporine as a primary therapy in inflammatory bowel disease probably
will remain unanswered until we have a sufficient number of years of follow-up on
a larger number of patients.

Joseph J. Nidiry, MDHarvard University College of MedicineWashington, D.C., USA